Analysis of daunorubicin and its metabolite daunorubicinol in plasma and urine with application in the evaluation of total, renal and metabolic formation clearances in patients with acute myeloid leukemia.

This report presents improved analysis methods of daunorubicin (DAUN) and its metabolite daunorubicinol (DAUNOL) in small volumes of plasma, as total and unbound concentrations, as well as in urine. This study also presents the pharmacokinetics of DAUN and DAUNOL in patients (n = 12) diagnosed with acute myeloid leukemia treated with intravenous DAUN (60 mg/m2/day, for three days). Serial blood and urine samples were collected up to 144 h after the beginning of the first infusion. The analytical methods presented no significant matrix effect. The linear ranges were 0.1-1000 ng/mL in plasma, 0.05-40 ng/mL in ultrafiltrate and 0.5-3000 ng/ml in urine. The precision and accuracy presented coefficients of variation and standard errors lower than 15 % in the three matrices. The methods allowed for the quantification of samples up to 144 h after the beginning of the first infusion. Unbound fractions for DAUN and DAUNOL were 23.91 % (17.33-32.99) and 29.23 % (25.84-33.07), respectively. The fraction recovered in urine was 4.40 % (3.87-5.03) for DAUN and 7.91 % (6.86-9.19) for DAUNOL. Total 292.96 L/h (261.74-327.90), renal 13.01 L/h (11.44-14.88), and hepatic 280.26 L/h (248.40-317.91) clearances of DAUN, as well as the DAUNOL formation clearance 23.41 L/h (19.09-28.97), were evaluated.

Total, renal and hepatic clearances of doxorubicin and formation clearance of doxorubicinol in patients with breast cancer: Estimation of doxorubicin hepatic extraction ratio.

Doxorubicin (DOX) is a cytotoxic drug which has remained as an essential component of chemotherapy regiment for breast cancer. The cardiotoxicity of DOX is related to the accumulation of its main metabolite doxorubicinol (DOXOL) in the cardiac tissue. Although the pharmacokinetics of DOX shows high interindividual variability, there are no significant covariates to improve dose adjustment. The present study reports the pharmacokinetics of both DOX and DOXOL in a homogeneous population of young female patients with breast cancer (n = 12) making use of a standardized drug association, evaluated in the very first chemotherapy cycle, using plasma and urine data that allowed the calculation of the renal clearance of DOX, the formation clearance of DOXOL and the hepatic clearance of DOX. The extensive data availability also made it possible to estimate the hepatic extraction ratio of DOX for the investigated population, as well as to determine DOXOL unbound fraction in plasma for the first time in humans. DOX and DOXOL simultaneous analysis in plasma, plasma ultrafiltrate, and urine were performed by liquid chromatography coupled to mass spectrometry (LC-MS/MS). The pharmacokinetics profile of both DOX and DOXOL showed high variability (geometric coefficient of variation of area under the plasma concentration versus time curve extrapolated to infinity was approximately 215 %). The geometrics means were 0.26 for DOXOL/DOX AUC ratio, 15 % and 17 % for unbound fractions of DOX and DOXOL, respectively, 30.70 L⋅h-1 for total clearance, 0.66 L⋅h-1 for renal clearance, 29.97 L⋅h-1 for hepatic clearance and 0.39 L⋅h-1 for the formation clearance of the metabolite DOXOL. The 95 % confidence interval of the estimated hepatic extraction ratio of DOX ranged from 0.14 to 0.79, which characterizes DOX as a drug of low, intermediate or high hepatic extraction ratio.

Clonal complexes 104, 109 and 113 playing a major role in the dissemination of OXA-carbapenemase-producing Acinetobacter baumannii in Southeast Brazil.

Carbapenem resistance among Acinetobacter baumannii strains isolated from clinical settings in Brazil has increased dramatically in the last 10 years due to the emergence and dissemination of OXA-type carbapenemase encoding genes. This study aimed to characterize the presence of carbapenem-hydrolyzing class D ß-lactamases (CHDL)-encoding genes and clonal complexes playing a major role in the dissemination of OXA-carbapenemase-producing A. baumannii in Southeast Brazil. A total of 74 A. baumannii strains isolated from patients admitted to 4 hospitals in Southeast Brazil were analyzed. Molecular characterization of strains revealed that 67 strains carried blaOXA-23 (72%), blaOXA-143 (25%) or both genes (3%). PFGE analysis identified 12 PFGE clusters, grouping 26 pulsotypes. Two PFGE clusters were predominant, comprising more than 66% of OXA-producing A. baumannii isolates. Among 23 representative strains characterized by MLST-UO (Multilocus Sequence Typing Scheme - University of Oxford, http://pubmlst.org/abaumannii/), 14 different STs were identified, of which six were confirmed as novel sequence types (designated as STs 402-407). Most of these isolates belonged to clonal complexes CC104,CC109 or CC113, whereas three STs were singletons (ST339, 403 and 407). In conclusion, the presence of blaOXA-23- and blaOXA-143-like genes was not related to specific ST/CC, suggesting that the dissemination of OXA-carbapenemase-encoding genes may involve different STs, in which the spread of OXA-23-like is most likely due to mobile elements (i.e., plasmids). In this regard, CC104, CC109 and CC113 played a major role as predominant CDHL-carrying clones, instead of CC92, which was not identified.